1. Field of the Invention
The present invention relates to methods of treating subjects with alveolar capillary membrane injury or methods of preventing alveolar capillary membrane injury in subjects, with the methods comprising administering to the subjects a therapeutically effective amount of ergothioneine and a pharmaceutically acceptable carrier. The invention also relates to methods of screening candidate compounds for their ability to mitigate the effects of alveolar capillary membrane injury.
2. Background of the Invention
Exposure to various insults frequently leads to alveolar capillary membrane injury (ACMI), which can result in such syndromes as Acute Respiratory Distress Syndrome (ARDS) and Acute Lung Injury (ALI). The alveolar capillary membrane is simply the thin tissue barrier between the alveolar sacs of the lungs and the pulmonary capillaries through which gases are exchanged. In addition, the alveolar capillary membrane is actively involved in solute and fluid flux between the alveolar surface, interstitium and the blood, as well as fluid clearance from the alveolar spaces to the interstitial spaces. See Gauzzi, M., Chest, 124(3): 1090-1102 (2003), incorporated by reference.
ARDS, the most severe form of ALI, is an often fatal, non-cardiogenic, acute, usually diffuse, edematous, hemorrhagic and/or inflammatory lung injury. For unknown reasons, ARDS can complicate infection, trauma, hyperoxia, radiation, hemorrhage, blast exposure, chemical exposure, pancreatitis, brain injury, smoke inhalation, transfusions, drug reactions and many other predisposing disorders including infection by CDC Category A-C pathogens. Individuals who sustain any of the predisposing disorders or conditions such as those listed above are considered to be at-risk for developing ALI and ARDS. See Repine, J. E., Lancet 339:466-469, (1992) and Ware, L. B. and Matthay, M. A., New Engl. J. Med. 29:2788-2796 (2005), both of which are incorporated by reference. ARDS often leads to multiple organ failure (MOF) and death. ARDS survivors also develop inexplicably develop post-traumatic stress disorder (Davydow), severe muscle weakness (Herridge) and other continuing disabilities with long-term consequences.
After initial injury of the alveolar capillary membrane, the progression to ALI and/or ARDS is unclear, but it appears to involve a cytokine triggered inflammation and oxidative stress involving mononuclear phagocytes (MNP), neutrophils (PMN) and xanthine oxidoreductase (XOR). ARDS patients and ARDS animal models have increased lung and blood cytokine levels, e.g., IL-1, IFN-γ, TNF-α and IL-8 and increased lung MNP, PMN and XOR levels, as well as deficiencies in lung glutathione (GSH) levels. See Repine (Lancet, 1992), Ware (New Engl. J. Med., 2005) and Bernard, G. R., et al., Chest, 112: 164-172 (1997). NF-κB is also activated in lungs and MNP of ARDS patients. Additionally, lipid peroxidation and carbonyl protein levels are generally increased in ARDS patients. Patients and animals with ARDS also exhale more hydrogen peroxide (H2O2). See Baldwin, S. R., et al., Lancet 1, 11-14 (1986) and Leff, J. A., et al., Am. J. Physiol. 265:L501-L506 (1993), both of which are incorporated by reference. While not especially toxic intrinsically, H2O2 often quickly forms highly toxic by-products, most notably a hydroxyl radical (.OH), produced by iron-catalyzed Fenton chemistry, hypochlorous acid. (HOCL) produced by reaction with myeloperoxidase (MPO)—a neutrophil component—and perhaps singlet molecular oxygen (1O2). The latter reactive species have appreciable toxicity and readily damage endothelial, epithelial and other cells in vitro.
Current treatments of ARDS are limited to physical treatments, such as ventilation, and there are currently no pharmaceutical therapies available that treat or remedy the root cause of ALI, ARDS or other syndromes associated with the development or acute or chronic consequences of alveolar capillary membrane injury. Indeed, according to the National Heart Lung and Blood Institute of the National Institutes of Health, the only medicinal treatments available for treatment of ARDS at this time appear to be limited to anti-infectives used for treating the pathogen infection and agents which provide supportive care, relieve pain or discomfort. See the world wide web at: nhlbi.nih.gov/health/dci/Diseases/Ards/Ards_WhatIs.html. In addition, ARDS is recognized as a disease that is extremely difficult to treat once it has started and become “established.” Mechanical ventilation is often associated with complications such as ventilator-associated pneumonia and ventilator-associate lung injury. These complications lead to significant morbidity in ALI and ARDS patient populations. Therefore, a treatment is needed that is effective, and not potentially harmful, even when given after exposure to an ARDS-inciting insult and after ARDS has started. At present, no such post-ARDS development therapy exists. Thus, there is a major need for the provision of the safe and effective treatment of alveolar capillary membrane injury.
Antioxidant defense may be pursued as a strategy for limiting the alveolar toxicity of reactive oxygen species associated with ALI and ARDS. Combating the effects of reactive oxygen species was once a promising area of study for those looking to limit the severity of, or potentially prevent, ALI and ARDS. While, N-acetylcysteine (NAC) and L-2-oxothiazolidine-4-carboxylate (Procysteine) have been most extensively studied, the results of human studies comparing NAC to placebo have been underwhelming. These unsatisfactory trials have led to little enthusiasm for conducting ongoing studies of antioxidant defense strategies for the treatment of ARDS. see Mark D. Siegel, MD, Novel therapies for the acute respiratory distress syndrome, UpToDate (Jan. 6, 2009 update), which is available on the world wide web at www.uptodate.com/online/content/topic.do?topicKey=cc_medi/18425&selectedTitle=5˜150 &source=search_result#22.
Similarly, a prophylactic therapy is also needed, such that the preventative could be given safely to individuals exposed to a potential insult before they develop ARDS. It is a particular need to have such a treatment readily available for use in the event of a mass casualty such as an explosive blast, a radiological insult, a toxic chemical exposure, inhalation of toxic fumes from fires or the like that could result in a large scale need for effective prevention or treatment of ARDS. At present, no such post-exposure (but pre-ARDS development) therapy exists. Accordingly, finding an ARDS therapy that was protective and/or useful in treating ongoing ARDS would be a new discovery. It is anticipated that ways will be developed to increase the ability to predict which at-risk individuals are more likely to develop ARDS and this information would then be used to institute therapies that can prevent ALI and ARDS development.